SUMMARY: Malaria, along with AIDS and tuberculosis, is one of the most devastating infectious diseases in the world. A cyclic paroxysm, characterized by sharp peaks of high fever, chills and rigors, is a pathognomonic sign of Plasmodium infection. The periodicity of malaria paroxysm is attributed to the simultaneous burst of millions of infected red blood cells (RBCs) carrying synchronous schizonts and relates to the intensity of malaria-induced cytokine storm. The underlying hypothesis is that parasite and host components expelled from bursting RBCs trigger various pattern recognition receptors and release of pyrogenic cytokines (e.g., IL-1? and TNF?). However, the mechanism that regulates parasite synchronization remains a major knowledge gap on Plasmodium biology. The scientific premise of this proposal is based on findings indicating that Pc synchronization follows the host circadian cycle; glucose is the immediate energy source for proliferation of Plasmodium blood stages; and systemic inflammation lead to a rhythmic hypoglycemia. Our experiments indicate that parasite arrest into non-replicative stages associates with hypoglycemia, whereas parasite proliferation occurs at the time of food intake. In addition, we found that the cyclic hypoglycemia is attenuated and parasite synchronization disrupted in TNF receptor (TNFR)-/- as well as clock genes (Clock-/-/Npas2-/- and Bmal1-/-) deficient mice. Bmal1 plays a key role as one of the positive elements in the mammalian autoregulatory transcription translation negative feedback loop, which is responsible for generating molecular circadian rhythms. Bmal1 becomes activate only in association with either Clock or Npas2. We hypothesize that by influencing inflammatory response and glucose metabolism, the host clock genes regulate synchronization of Pc blood stages. This proposal will make substantial contributions to the understanding of the process by which malaria blood stages synchronize with the vertebrate host circadian cycle. We propose to investigate two main topics that are either unresolved or completely novel: (i) the mechanism by which TNF? controls glycemia and synchrony of Plasmodium cell cycle; and (ii) the importance of clock genes that control central and peripheral circadian cycle, on inflammation, glycemia and parasite synchronization in Pc-infected mice. We expect that these findings have important applications for future development of immune- and metabolic-based interventions in malaria patients.